New Synthetic Methodologies for Carbon−Carbon Double Bond

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Acc. Chem. Res. 1998, 31, 584-592

New Synthetic Methodologies for Carbon-Carbon Double Bond Formation YANCHANG SHEN Shanghai Institute of Organic Chemistry, Academia Sinica, 354 Fenglin Lu, Shanghai 200032, China Received October 7, 1997

Carbon-carbon double bond formation is one of the useful and fundamental reactions in synthetic organic chemistry, particularly in the synthesis of complex natural products with biological activity. In 1953 Wittig and Geiser found that methylenetriphenylphosphorane reacted with benzophenone to give 1,1-diphenylethene and triphenylphosphine oxide, leading to the development of a new olefination methodology universally known as the Wittig reaction.1 Since then the Wittig olefination has found widespread application in synthetic organic chemistry, and numerous papers and reviews have detailed the progress of the Wittig reaction.1 Therefore, an investigation of the new synthetic methodology for carbon-carbon double bond formation should be valuable, and this Account reviews recent developments in our laboratory.

Synthetic Utility of Fluorinated β-Ketophosphonium Salts The well-known Wittig reaction involves a nucleophilic attack by the ylide carbon of the Wittig reagent on electrophiles, forming a carbon-carbon double bond.

Alternatively, in our reaction the β-ketophosphonium salts as reagents are attacked by nucleophiles, resulting in the formation of a fluorinated carbon-carbon double bond.

Yanchang Shen, born in Shanghai, China, in 1931, received his B.S. (1953) in chemistry from Fu Dan University and did his graduate study (1963-1967) at the Shanghai Institute of Organic Chemistry, Academia Sinica (with Professor Y. Z. Huang). He was a postdoctoral associate at the University of Massachusetts (with Professor Ernest I. Becker, 1981-1982) and a Visiting Professor at Clemenson University (1989-1990). He was appointed Associate Professor and Professor at the Shanghai Institute of Organic Chemistry, Academia Sinica, in 1981 and 1986, respectively. He became Editor-in-Chief of Acta Chim. Sin., Chinese Chemical Society, in 1994. In 1995 he received the Natural Science Award (first class) of Academia Sinica for creative work in new synthetic methodology for carbon-carbon double bond formation. His research interests include development of new synthetic methodology using phosphorus, arsenic, and organometallic reagents. 584

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This reaction is a new contribution to carbon-carbon double bond synthesis, particularly useful for the synthesis of fluorinated functionalized carbon-carbon double bond compounds, which are useful intermediates in the synthesis of fluorinated biologically active compounds and would be difficult to prepare otherwise. Usually, fluorinated ylides are unable to react with aldehydes or ketones because of the strong electron-withdrawing effect of the perfluoroalkyl group.2 The new idea of this reaction is to make clever use of the strong electron-withdrawing property of the perfluoroalkyl group, resulting in the formation of a δ positive charge on the neighboring carbonyl carbon. Easy attack of nucleophiles at the carbonyl carbon, followed by elimination of triphenylphosphine oxide, leads to the formation of a carbon-carbon double bond. The nucleophiles can be a variety of organometallic reagents, leading to a reaction of wide scope. The phosphoranes 1, generated from the corresponding phosphonium salts and phenyllithium, were acylated by the addition of perfluoroalkanoic anhydride to give fluorinated β-ketophosphonium salts 2, which in the reaction medium were attacked by nucleophiles (RLi) (Scheme 1). Elimination of the triphenylphosphine oxide gave tetrasubstituted fluoroolefins 3 in 42-70% yields.3 When substituted lithium acetylides were utilized as nucleophiles, fluoroenynes 4 were obtained in 43-80% yields.4 This reaction is of broad scope since R1 and R2 may be alkyl, aryl, allylic, benzylic, or alicyclic groups. They would be expected to be useful intermediates in the synthesis of fluorine-containing biologically active compounds. When methylenetriphenylphosphorane as a nucleophile attacked fluorinated β-ketophosphonium salts, after deprotonation and elimination of triphenylphosphine oxide, new ylides 7 were formed which reacted with aldehydes to give fluorodienes 8 with exclusively Eisomers in 20-58% yields (Scheme 2).5 After the addition of Ph3PdCH2 to 5, the temperature of the reaction mixture must be maintained at -78 °C to avoid elimination of triphenylphosphine oxide, prior to deprotonation of 6. After addition of PhLi to 6, the reaction mixture was gradually brought to 25 °C wherein the triphenylphosphine oxide was spontaneously eliminated. If the reaction mixture containing 6 is warmed before the addition of PhLi, a mixture of elimination products 9 and 10 results via two alternative pathways (a and b in Scheme 3). Thus, the regiocontrolled elimination of triphenylphosphine oxide from deprotonated 6 is important for forming 7 exclusively. The ylides 11, generated by the same method as 7, were acylated by the addition of perfluoroalkanoic anhydride, after transylidation, to give the stabilized ylides 12 (Scheme 4). Vacuum pyrolysis of 12 gave conjugated diperfluoroalkyl enynes 13 in 85-94% yields which would be difficult to prepare otherwise.6 Methylenetriphenylarsorane also readily added to the carbonyl group of fluorinated β-ketophosphonium salt 5 S0001-4842(97)00060-5 CCC: $15.00

 1998 American Chemical Society Published on Web 06/13/1998

New Methodologies for C-C Double Bond Formation Shen

Scheme 1

Scheme 5

Scheme 2 Scheme 6

Scheme 7

Scheme 3

Scheme 8

Scheme 4

(Rf ) CF3),7 after deprotonation and elimination of triphenylphosphine oxide, giving ylide 14, which reacted with aldehydes to give trans-fluorovinylic epoxides 15 stereospecifically in 35-63% yields (Scheme 5). Upon reaction of ylide 14 with acrylates, trifluoromethylated vinylcyclopropanes 16 were obtained exclusively

as the trans-isomer in 43-62% yields (Scheme 6).8a Ylide 14 could also be utilized in the synthesis of fluorinated diene esters or amides as shown in Scheme 7. Treatment of bromoacetic esters or amides with ylide 14 gave trifluoromethylated 2,4-dienyl carboxylates in 43-69% yields8b or 2,4-dieneamides in 45-85% yields,8c respectively, exclusively as the E-isomers. In addition to lithium reagents zinc reagents are also useful as nucleophiles to attack fluorinated β-ketophosphonium salts. Reaction of organozinc compounds with fluorinated β-ketophosphonium salts 2 gave trifluoromethylated β,γ-unsaturated esters and nitriles 20 in 2684% yields (Scheme 8).9 Use of unsaturated organozinc compounds with fluorinated β-ketophosphonium salts 2 provides a route to perfluoroalkylated 1,4-alkadienes.10 In the case of Rf ) VOL. 31, NO. 9, 1998 / ACCOUNTS OF CHEMICAL RESEARCH

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Scheme 9

Scheme 10

Scheme 11

CF3, two regioisomers, 23 and 24, were isolated (41-55% yields; 23:24 ) 73-95:27-5), while in the case of salts with longer chain perfluoroalkyl groups, only one isomer, 23, was obtained (37-43% yields) (Scheme 9). Thus, steric effects are clearly important in the regioisomer distribution. The nucleophiles employed to attack fluorinated β-ketophosphonium salts are not limited to carbon, and heteronucleophiles can also be utilized. When diethyl lithium phosphite was reacted with 2, (R-fluoroalkylvinyl)phosphonates or (R-fluoroepoxyalkyl)phosphonates were isolated depending upon the groups R1 and R2 in 2 and the base used (Scheme 10).11 Usually the (R-fluoroalkylvinyl)phosphonates 26 were obtained exclusively in 4178% yields, but in the case of R1 ) R2 ) CH3 and with methyllithium as a base, (R-fluoroepoxyalkyl)phosphonates 25 were isolated exclusively in 42% yields. The mechanism may be rationalized as shown in Scheme 11.11 The reaction is initiated by nucleophilic attack of diethyl lithium phosphite on the carbonyl carbon 586 ACCOUNTS OF CHEMICAL RESEARCH / VOL. 31, NO. 9, 1998

Scheme 12

atom of 2 to give the intermediates 27 and 28. There is a dynamic equilibrium in 27 and 28, and the formation of 25 against 26 is in direct proportion to the relative transition state energies for the two reactions. If R1 ) R2 ) CH3, the transition state energy of 27 is low and the oxygen anion with the least sterically hindered position attacks the neighboring carbon atom, followed by elimination of triphenylphosphine to give 25. In the other cases, with a more bulky R1 group, the transition state energy of 28 is low and subsequent decomposition of the betaine 28 with elimination of triphenylphosphine oxide in a syn fashion affords 26. Among phosphoryl-stabilized carbanions, allylic phosphonates occupy an important position.12a Trifluoromethylated allylic phosphonates are of special interest. They can be synthesized by a one-pot reaction of [(dialkoxyphosphinoyl)methyl]lithium with trifluoromethylated β-ketophosphonium salts in 56-72% yields (Scheme 12).12a When R1 ) Ph and R2 ) CH3, the Z-isomer is obtained exclusively. The high stereoselectivity of the reaction can be rationalized. Thus, the oxygen of the carbonyl group orientates itself between the small (CH3) and medium (Ph) sized groups, and the large group (Ph3P+) orientates itself anti to the carbonyl oxygen. The reaction is initiated by nucleophilic attack of a nucleophile on the carbonoxygen double bond of the carbonyl group and for the additions containing an asymmetric R-carbon, the FelkinAnh model of asymmetric induction12b predicts the predominant diastereomer. The incoming nucleophile preferentially attacks the less hindered side of the plane containing the CdO bond. Therefore, the relative steric bulks of Ph and CH3 play an important role in the stereoselectivity. The relative steric bulk of CH3 is smaller than that of Ph. The attack is from the rear (the side of the plane containing the small group) of 30, forming the intermediate 31a, and after rotation at the C-C bond, intermediate 32a is formed, while the reverse is true for the attack from the front, forming intermediates 31b and then 32b. Each of those intermediates decomposes via a syn elimination, affording (Z)-29 or (E)-29 (Scheme 13). In our cases, formation of 31a was favored over 31b and the Z-isomer was obtained exclusively. Due to their useful biological activity in medicinal and agricultural chemistry, heterocyclic compounds containing fluorine have received much attention.13,14 However, only a few reports have appeared in the literature concerning the fluoroalkylation of heterocyclic rings.15 We found that heterocyclic lithium compounds could attack β-ketophosphonium salts, leading to the regiospecific introduction of a fluorovinyl group into the heterocyclic rings in 51-84% yields (Scheme 14).15,16 Sulfur-containing nucleophiles were also useful in attacking β-ketophosphonium salts. The ease of synthesis

New Methodologies for C-C Double Bond Formation Shen

Scheme 13

Scheme 17

Scheme 18

Scheme 14

Scheme 15

Scheme 16

of 1,3-dithiane derivatives combined with their versatile chemistry has attracted much attention in their use as synthons.17 We found that the reaction of 2-lithio-1,3dithiane with fluorinated β-ketophosphonium salts 2 gave a new fluorinated synthon, perfluoroalkylated vinyl 1,3dithianes 36, in 52-92% yields (Scheme 15).17 Allylic sulfides are potentially useful intermediates in organic synthesis and can undergo many useful organic transformations.18 Perfluoroalkylated allylic sulfides 37 could be synthesized conveniently by the reaction of (thiophenoxymethyl)lithium with fluorinated β-ketophosphonium salts in 51-72% yields (Scheme 16).19 Grignard reagents, such as BunMgBr, PhCtMgBr, and PhCH2MgCl gave the tetrasubstituted fluoroolefins when

used with fluorinated β-ketophosphonium salts,20 similar to organolithium compounds. However, when phenyl Grignard reagent or Na-Hg was used, reductive cleavage of the fluorinated β-ketophosphonium salts 2 occurred instead of nucleophilic addition.20,21 The enolates 38 have been successfully trapped by suitable electrophiles and exhibit normal enolate reactivity in relation to their Oand C-nucleophilicity. Compounds 38 react with acyl chlorides and aldehydes to give unique fluorinated β-hydroxy ketones 39 in 82-88% yields or vinyl esters 40 in 56-94% yields, respectively (Scheme 17). Reaction with benzyl bromide gave fluorinated vinyl ether 41 and ketone 42 in 65% yields. When one of the groups (R1, R2) in the alkylidene moiety of 2 is an electron-withdrawing group (43, X ) CO2Et) or electron-donating group (43, X ) OAr), the lithium reagents regiospecifically attack the carbonyl group attached to the trifluoromethyl group, affording trifluoromethylated R,β-unsaturated esters in 40-66% yields22 or vinyl ethers in 40-85% yields23 as the E-isomer exclusively or as the major product (E:Z ) 95-61:5-39) (Scheme 18). Treatment of fluorinated β-ketophosphonium salts 2 with aqueous sodium hydroxide (5%) gave perfluoroalkyl alkyl ketones 45 in 37-78% yields (Scheme 19).24

“One-Pot” Carbon-Carbon Double Bond Formation The well-known Wittig reaction can provide olefins with both regio- and stereoselectivity, especially in the synthesis VOL. 31, NO. 9, 1998 / ACCOUNTS OF CHEMICAL RESEARCH

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Scheme 19

Scheme 22

Scheme 20

Scheme 23

Scheme 24 Scheme 21

of a variety of naturally occurring substances. However, this reaction requires three steps, i.e., preparation of salts, ylide formation, and reaction with carbonyl compounds. We found that, in the presence of suitable catalysts (Pd, Zn, or Cd), trialkylphosphines and arsines are effective reagents for “one-pot” carbon-carbon double bond formation between R-bromo carboxylic derivatives (esters, amides, and nitriles) and aldehydes (Scheme 20). R,βUnsaturated esters in 52-97% yields,25,26,27,28 amides in 30-86% yields,29,30 and nitriles in 55-77% yields31 were obtained. The geometry of the newly formed double bond in 46 was exclusively E 25,26,28-30 or predominantly E (E:Z ) 88-68:12-32)27 in the esters and amides. In the absence of trialkylphosphine (arsine) or catalyst (Pd, Zn, or Cd), olefination did not occur at all. It is noteworthy that this reaction greatly simplifies the traditional Wittig reaction into a stereospecific alkenylation methodology and compresses the three steps of a Wittig reaction into a one-step, one-pot synthesis.25,32 R,β-Unsaturated nitriles could also be synthesized from the iodine-catalyzed reaction of chloroacetonitrile with aldehydes promoted by tri-n-butylarsine and magnesium in 73-81% yields.33 Our approach was successfully extended to the synthesis of fluorinated analogues, R-fluoro R,β-unsaturated esters in 52-90% yields34 and amides in 45-68% yields.35 On treatment of R-fluoro R-iodo ester or amide with aldehydes in the presence of trialkylarsine and a catalytic amount (10 mol %) of Pd(PPh3)4, R-fluoro R,β-unsaturated esters or amides were obtained (Scheme 21). In the case of esters, a mixture of E- and Z-isomers was obtained (E:Z ) 33-46:67-54), while in the case of amides, the Z-isomer was obtained predominantly (Z:E ) 95-71:5-29). Without catalyst, active bromo compounds readily reacted with aldehydes in the presence of tri-n-butylarsine in a one-pot reaction, forming a carbon-carbon double bond in 68-96% yields.36 The reaction of bromocyanoacetic ester with aldehydes in the presence of tri-nbutylarsine under neutral conditions gave R,β-unsaturated cyano esters exclusively as the E-isomer in 76-98% yields (Scheme 22).37 588 ACCOUNTS OF CHEMICAL RESEARCH / VOL. 31, NO. 9, 1998

Treatment of aldehydes and ethyl (R-diethoxyphosphoryl)bromoacetate with an equivalent amount of trin-butylarsine gave R-carboethoxy R,β-unsaturated phosphonates in 62-92% yields (Scheme 23). The geometry of the newly formed double bond in 50 was exclusively E.38 It is of interest that aldehydes reacted with bromonitromethane in the presence of tri-n-butylarsine to afford substituted 1-bromo-1-nitroalkenes in 62-69% yields with Z-stereoselectivity (Scheme 24).39

A Novel Ylide-Anion Formation Resulting from Nucleophilic Addition Ylide-anions with high reactivity were first reported by Corey and King, using sec- or tert-butyllithium as a base to deprotonate the ylide, methylenetriphenylphosphorane, and then to react with substrates of low reactivity such as epoxides or hindered ketones.40 We found that a novel fluorinated ylide-anion formation with high reactivity results from nucleophilic addition of organometallic reagents (lithium reagents, Grignard reagents). This new method is different from Corey’s method (deprotonation method) since it results from nucleophilic addition of organometallic reagents and it provides a method for the utilization of the very stable fluorinated ylide in alkene synthesis. Due to the powerful electron-withdrawing effect of the trifluoroacetyl group, [(trifluoroacetyl)methylene]triphenylphosphorane 52, the more reactive arsorane is very stable and unable to react with aldehydes.2 An attempt to activate this phosphorane by nucleophilic addition of n-butyllithium to a carbonyl group succeeded because the reactivity of the carbonyl group neighboring the trifluoromethyl is enhanced. In this case the n-butyllithium attacks 52 to give an ylide-anion 53 which reacts with aldehydes to afford trans-R-trifluoromethyl allylic alcohol 54 exclusively in 46-55% yields after hydrolysis (Scheme 25).41 [3-(Trifluoroacetyl)allylidene]triphenylphosphorane 55 was very stable and unreactive with aldehydes due to the strong electron-withdrawing effect of the trifluoroacetyl group. The use of n-butyllithium or phenyllithium to activate ylide 55 resulted in a reaction different from the previous case. Thus, the nucleophiles attack in a conju-

New Methodologies for C-C Double Bond Formation Shen

Scheme 25

Scheme 28

Scheme 26 Scheme 29

Scheme 27

gate manner to give ylide-anions 56 which react with aldehydes, after hydrolysis, to afford trans-R,β-unsaturated trifluoromethyl ketones 57 exclusively in 46-92% yields (Scheme 26).42 An allylic ylide-anion, generated from allylidenetriphenylphosphorane and n-BuLi-TMEDA reacted readily with carbonyl compounds, affording β-hydroxy 1,3-dienes as the unique E,E-isomers in 39-58% yields.43 1-Iodo-1-(trimethylsilyl) 1,3-dienes could be conveniently synthesized with high stereoselectivity by consecutive reaction of allylidenetriphenylphosphorane in 47-85% yields.44 (Dicarbonylmethylene)triphenylphosphoranes are very stable because of the strong electron-withdrawing effect of the two carbonyl groups and are unreactive with aldehydes or ketones. A means to use the fluorinated (dicarbonylmethylene)triphenylphosphoranes as reagents in Wittig reactions was of interest. Fluorinated (dicarbonylmethylene)triphenylphosphoranes 58 could be regiospecifically attacked at the perfluoroacyl groups by various lithium reagents to form ylide-anions 59 (Scheme 27). After protonation, the intramolecular Wittig reaction took place spontaneously to give perfluoroalkylated R,β-

unsaturated carbonyl compounds 61 in 90-97% yields with high E-stereoselectivity (E:Z ) 100-67:0-33)45 and perfluoroalkylated R,β-unsaturated amides in 74-90% yields.46 R,β-Unsaturated acids 61 (X ) OH) are readily synthesized via ylide-anion formation and hydrolysis (KOH/H2O-MeOH) from 58 (X ) OMe) in 90-95% yields.47 Similarly perfluoroalkylated R,β-unsaturated nitriles 62 could be synthesized via ylide-anion formation from [(perfluoroacyl)cyanomethylene]triphenylphosphoranes in 90-98% yields with high E-stereoselectivity (E:Z ) 10086:0-14).48

The ylide-anions 64 resulting from nucelophilic addition of lithium reagents react with N-bromosuccinimide or N-chlorosuccinimide, affording perfluoroalkylated R-bromo or R-chloro R,β-unsaturated esters or nitriles 66 in 6290% yields (Scheme 28).49,50 The nature of the substituents in the chloroalkenes may play an important role in determining the stereoselecivity of the reaction. It can be rationalized as shown in Scheme 29. The reaction is initiated by electrophilic attack of NCS on the ylide-anion, forming two diastereoisomeric betaines 65a and 65b in equilibrium. The energies of the betaines depend on the steric interference between the individual pairs of “eclipsed” substituents. As a result of the different energies of betaines the equilibrium can shift VOL. 31, NO. 9, 1998 / ACCOUNTS OF CHEMICAL RESEARCH

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Scheme 30

Scheme 32

Scheme 31

toward isomer 65a or 65b. The relative steric bulk of CF3 and R groups, and hence their interaction with Cl and R′, seems to control the stereochemical results. In the case where R′ ) CO2Bu-t, a bulky group, the ratio of E-isomer decreases as the group size R is decreased (R ) sec-Bu, E:Z ) 100:0; R ) n-Bu, E:Z ) 73:27; R ) PhCt C, E:Z ) 30:70). In the first case, the largest groups (secBu, CO2Bu-t) are located trans with respect to one other in intermediate 65a, and the resulting preferred conformation with lower energy undergoes decomposition to give the E-isomer, while in the last case the location of the largest groups (CF3 and CO2Bu-t) in a trans configuration in intermediate 65b resulted in the conformation with somewhat lower energy which undergoes decomposition to give a mixture of two isomers. An attempt to react ylide-anions 67 with N-iodosuccinimide failed. However, they did react with either iodine or 1,2-diiodoethane, giving perfluoroalkylated R-iodo-R,βunsaturated nitriles in 70-97% yields (Scheme 30).51

synthesized by way of fluorinated β-ketophosphonium salts (Scheme 18)22 and via the formation of ylide-anions (Scheme 27).45 Similarly the E-isomer was obtained as the major product in the preparation of perfluoroalkylated R,β-unsaturated nitriles.48 Further, only E-stereoselectivity was observed in the synthesis of perfluoroalkylated R,βunsaturated esters from ylide-anions 70 generated from phenyl Grignard reagent and fluorinated dicarbonyltriphenylphosphoranes.53 All these methodologies gave predominantly E-isomers. Recently we found a novel conversion of E-stereoselectivity to Z-stereoselectivity in the synthesis of trifluoromethylated R,β-unsaturated esters and nitriles by way of O-methylation of an ylide-anion.54 Reaction of fluorinated phosphoranes 72 with organolithium reagents gave the ylide-anions 73, which, after protonation and elimination of triphenylphosphine oxide, afforded (E)-75 as the major products (E:Z ) 100-88:0-12) in 88-98% yields (Scheme 32). Before protonation, the ylide-anions 73 were allowed to react with methyl iodide to afford Omethylated products 74 which could be hydrolyzed by acetic acid to give (Z)-75 as the major products (Z:E ) 92-62:8-38) in 85-94% yields. The Z- and E-isomers could be separated conveniently by column chromatography on silica gel or by fractional distillation.

Stereocontrolled Olefination Methodology

Concluding Remarks

Control of the stereochemistry is very important in the synthesis of unsaturated natural products with biological activity.52 Therefore, the development of an effective method for stereocontrolled olefination should be valuable. Fluorinated dicarbonyltriphenylphosphoranes 69 reacted with a variety of Grignard reagents to give the ylideanions 70 (Scheme 31). Treatment of 70 with saturated aqueous methylamine hydrochloride, followed by elimination of triphenylphosphine oxide, gave trifluoromethylated R,β-unsaturated esters 71, with the Z-isomers being the major products in 85-94% yields (Z:E ) 94-90:610), while treatment of 70 with 5% aqueous hydrochloric acid under the same conditions afford predominantly the E-isomer of 71 in 72-95% yields (E:Z ) 100-75:0-25).53 Perfluoroalkylated R,β-unsaturated esters with the Eisomers as the major products could be conveniently

The fluorinated β-ketophosphonium salts can be utilized as reagents for the synthesis of a great variety of functionalized perfluoroalkylated alkenes. Examples are fluoroalkenes, fluoro enynes, fluoro dienes, bis(perfluoroalkyl) enynes, fluorovinylic epoxides, trifluoromethylated vinylcyclopropanes, trifluoromethylated R,β- and β,γ-unsaturated esters, perfluoroalkylated alkadienoic esters and amides, perfluoroalkyl alkyl ketones, perfluoroalkylated vinyl and allylic phosphonates, phosphoryl fluoroepoxides, fluoroalkyl phenyl sulfides, fluorovinyl heterocyclic compounds, fluorovinyl dithianes, perfluoroalkylated vinyl esters, perfluoroalkylated β-hydroxy ketones, perfluoroalkylated vinyl ethers, and perfluoroalkylated 1,4-dienes. These compounds would be difficult to prepare by other methods. A fluorine atom or perfluoroalkyl group substituted in compounds can often enhance their biological activity, and organofluorine compounds have been ap-

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New Methodologies for C-C Double Bond Formation Shen

plied increasingly in pharmaceuticals, agrochemicals, and other fields, as exemplified in vitamin A and pheromone chemistry.8b,c,34,54b R-Fluoro R,β-unsaturated esters (48) have been used successfully as intermediates in the synthesis of monofluorinated retinoids, insect sex pheromones, and pyrethroids.34,54b Therefore, they would be useful intermediates for the synthesis of fluorine-containing biologically active compounds, particularly in the field of medicinal and agricultural chemistry. “One-pot” carbon-carbon double bond formation methodology greatly simpifies the traditional Wittig reaction into a stereospecific alkenylation methodology and compresses the three steps of a Wittig reaction into a onestep, one-pot synthesis. A novel ylide-anion formation, which is different from Corey’s deprotonation method and results from nucleophilic addition of organometallic reagents, was found. This method provides a means of using very stable fluorinated ylides in the synthesis of functionalized perfluoroalkylated alkenes. Stereocontrolled olefination methodology includes a conversion of E-stereoselectivity to Z-stereoselectivity in the synthesis of trifluoromethylated R,β-unsaturated esters and nitriles by way of O-methylation of a ylide-anion. In summary, all these new synthetic methodologies for carbon-carbon double bond formation with high stereoselectivity are potentially a useful approach in organic synthesis particularly in the fields of medicinal and agricultural chemistry for the synthesis of biologically active compounds. I much appreciate my able graduate students and colleagues, whose names are cited in the references, for their contributions, which made all of this possible. The funding for this research has come from the National Natural Science Foundation of China, Laboratory of Organometallic Chemistry, and Academia Sinica.

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